Elsevier

Biological Psychiatry

Volume 59, Issue 12, 15 June 2006, Pages 1236-1239
Biological Psychiatry

Brief report
Microinjection of the L-Type Calcium Channel Antagonist Diltiazem into the Ventral Nucleus Accumbens Shell Facilitates Cocaine-Induced Conditioned Place Preferences

https://doi.org/10.1016/j.biopsych.2005.09.024Get rights and content

Background

Calcium (Ca2+) influx within the nucleus accumbens shell (NASh) can influence brain reward processes. We found previously that rats self-administer NMDA receptor antagonists (which block Ca2+ influx through NMDA receptors) into the NASh. We also found that manipulations which increase expression of Ca2+-permeable AMPA receptors within this region make cocaine aversive. Here we examined if Ca2+ influx via L-type Ca2+ channels within the NASh would influence cocaine reward.

Methods

Rats received bilateral microinjections of the L-type Ca2+ channel antagonist diltiazem into the ventral NASh prior to place conditioning with systemic cocaine.

Results

Microinjections of diltiazem (10 nmol/hemisphere) into the ventral NASh facilitated the ability of a sub-threshold dose of cocaine (5.0 mg/kg) to establish place preferences, but did not affect place conditioning on their own (5.0–40 nmol/hemisphere). Microinjections into more dorsal regions had no effects.

Conclusions

Blockade of Ca2+ influx through L-type channels Ca2+ within the ventral NASh increases cocaine reward.

Section snippets

Animals and Surgery

Sixty-two male Sprague Dawley rats (300–325 g) (Charles River, Boston, Massachusetts) were used. Rats were housed individually with free access to food and water, and were maintained on a 12-hour light (0700–1900) dark cycle. Rats were anesthetized with intraperitoneal (IP) pentobarbital (65 mg/kg) supplemented with subcutaneous atropine (.25 mg/kg) to minimize bronchial secretions. Bilateral guide cannula (26-gauge) aimed 1 mm above the ventral NASh (1.5 mm anterior to bregma, ±1.0 mm from the

Results

A dose-response function for cocaine alone (5.0–20 mg/kg, IP) with intra-NASh microinjections of vehicle prior to cocaine conditioning showed that rats spent more time in cocaine-associated environments following conditioning (F1,15 = 11.7, p < .01) (Figure 1). Only rats given 20 mg/kg cocaine spent more time in cocaine-associated environments after conditioning (p < .01, Fisher’s protected t-tests). Lower doses of cocaine (5.0 and 10 mg/kg, IP) did not produce reliable effects. These data are

Discussion

Microinjections of diltiazem (10 nmol/hemisphere) into the ventral NASh shell immediately prior to systemic injection of a sub-threshold dose of cocaine (5.0 mg/kg, IP) established conditioned place preferences. The doses of diltiazem and cocaine used in combination did not have significant effects when tested alone. These effects were specific to the ventral NASh because microinjections of diltiazem into more dorsal regions did not enhance the ability of this sub-threshold dose of cocaine to

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      For example, CaV1.2 LTCCs in the NAc has been implicated in the expression of psychostimulant sensitization via recruitment of Ca2+/calmodulin-dependent kinase leading to increased surface expression of AMPA receptors in MSNs (Anderson et al., 2008; Schierberl et al., 2011). Intra-NAc administration of diltiazem, a non-dihydropyridine LTCC blocker, has been reported to suppress cocaine priming-induced reinstatement of cocaine seeking after extinction (Anderson et al., 2008), while facilitating the development of cocaine CPP (Chartoff et al., 2006). These results using diltiazem may have to be interpreted with caution, as its effect on neuronal LTCCs, especially the CaV1.3 subtype, has not been confirmed with electrophysiological recordings in neuronal preparations.

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      In rats, administration of the hydrophobic dihydropyridine LTCC antagonist isradipine dose-dependently attenuates intake of sweetened drinking water, a rewarding liquid (Calcagnetti and Schechter, 1992), as well as the reinforcing effects of amphetamine (Pucilowski et al., 1995), while nimodipine suppresses the effect of nicotine (Biala, 2003) in conditioned place preference. Additionally, there is evidence that the LTCC antagonist D-cis-diltiazem enhances the rewarding effects of cocaine in the conditioned place preference test when injected in the ventral NAc shell (Chartoff et al., 2006). In mice sensitized to psychostimulants, increases in Cav1.2 protein levels in the frontal cortex and limbic forebrain were found (Ford et al., 2009; Shibasaki et al., 2010), as well as increased surface expression of Cav1.2 channels in pyramidal neurons of the medial prefrontal cortex (Ford et al., 2009).

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      Under normal circumstances, excitatory influences mediated by glutamate actions at AMPA and NMDA receptors or dopamine actions at D1-like receptors are balanced by inhibitory dopamine actions at D2-like receptors. Treatments that would be expected to reduce activity in the NAc – including cocaine (Peoples et al., 2007), morphine (Olds 1982), NMDA antagonists (Carlezon and Wise, 1996), L-type Ca2+ antagonists (Chartoff et al., 2006), palatable food (Wheeler et al., 2008) and expression of dominant-negative CREB (Dong et al., 2006) – have reward-related effects because they reduce the inhibitory influence of the NAc on downstream reward pathways. In contrast, treatments that activate the NAc by amplifying glutamatergic inputs (e.g., elevated expression of GluR1; Todtenkopf et al., 2006), altering ion channel function (e.g., elevated expression of CREB: Dong et al., 2006), reducing inhibitory dopamine inputs to D2-like cells (e.g., κ-opioid receptor agonists), or blocking inhibitory μ- or δ-opioid receptors (West and Wise, 1988; Weiss, 2004) are perceived as aversive because they increase the inhibitory influence of the NAc on downstream reward pathways.

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